Autoimmune nephritis is a leading cause of chronic kidney disease and renal failure worldwide and a major source of allograft injury and loss. Yet available therapies are limited to nonspecific toxic regimens. Antigen- and cell-specific therapies hold great promise but development of these novel mechanism-based interventions requires understanding of underlying pathogenesis. The proposed research will determine tolerance mechanisms that regulate nephritogenic lymphocytes with a focus on autoantibodies and B cells. An overarching hypothesis is that commonalities exist in the processes maintaining tolerance in kidney-restricted and systemic autoimmunity. Aim 1 uses a novel antibody (Ig) transgenic (Tg) model that targets the Goodpasture antigen to test the hypotheses that: i) B cells recognizing pathogenic epitopes on collagen are regulated in vivo;ii) alpha3(IV)NC1 collagen is a tolerogen, and iii) a subset of anti-alpha3(IV)NC1 B cells readily evade or escape tolerance. Immune phenotype will be measured in transgenic and informative mutant backcross strains. Aim 2 will determine the role of genetic autoimmune susceptibility in altering the fate of nephrotropic B cells. This aim tests the hypothesis that host modifier genes modulate tolerance at cellular and molecular levels. These studies are possible because the LamH Ig Tg with a well characterized tolerance phenotype has been established on lupus-prone strains MRL, NZB and BXSB, each of which carries a unique constellation of disease susceptibility genes and develops severe nephritis similar to disease in man. Immune phenotype will be measured and compared in these and the related BWF1 Tg strain. The regulatory role of galectins 1 and 3, prominent proteins only recently identified as modifiers of B cell tolerance, will be determined using genetic galectin deficiency. Finally the relevance to human autoimmunity of key regulatory molecules or pathways, determined by oligoarray to maintain B cell anergy in B6 or lupus MRL mice, will be explored through probing existing array databases. It is anticipated that mechanistic insight into regulation of nephritogenic autoimmunity will yield new targets for therapy in immune nephritis. PUBLIC HEALTH RELEVANCE: Autoimmune diseases affect ~6% of the population, and when manifest in the kidney as glomerulonephritis, constitute a leading cause of chronic kidney disease and the single most common cause of end stage renal disease worldwide. Glomerulonephritis also accounts for up to 50% of kidney transplants, over 8% of which are ultimately loss to recurrent disease. Our studies are designed to dissect the tolerance mechanisms that regulate renal autoimmunity, as well as defects that lead to disease. Each of these checkpoints is a potential target for newer more disease specific therapies.